The Alcohol Research Center of The Scripps Research Institute (TSRI-ARC) proposes to continue its interdisciplinary program focused on the theme of the central nervous system effects of alcohol. For this renewal application, the TSRI-ARC will be a P60 consisting of 9 components plus an Educational Component. Four core components are proposed: Administrative, Animal Models Development, Biochemical and Pilot. Five research components are proposed: Cellular Neurobiology (Roberto/Siggins), Neuroendocrinology (Rivier), Neuropharmacology Neuropeptides (Zorrilla/Weiss), Neuropharmacology Endocannabinoids (Parsons), and Clinical Neurobehavioral (Ehlers). The overall hypothesis of the TSRIARC is that the function of specific neurotransmitter synapses in select parts of the reward and stress systems that are compromised by chronic ethanol administration account for the development of vulnerability to alcoholism in genetically prone individuals. Two major themes have emerged from our present research 1) the neuropharmacological mechanisms of vulnerability to dependence depend on how specific brain reward and stress circuits change during the transition from initiation of drinking to binge drinking to dependence (Specific Aims 1 &2); 2) the neuropharmacological changes produced by binge drinking in adolescents and young adults may drive excessive drinking and vulnerability to dependence in adults (Specific Aim 3). Progress during the previous funding period has led to a focus on understanding dependence-induced neuroadaptive mechanisms and residual allostatic changes that persist following acute abstinence. The new focus of the ARC is on neuroadaptive changes that are engaged by binge drinking that form a transition from initiation of drinking to dependence and form a crucial part of the basis for inheritable susceptibility to human alcoholism. The TSRI-ARC also supports the Center at Large, which includes: seventeen NIAAA R01's, two U01's, four NIAAA R21's, two NIAAA R37 awards, one NIAAA T32 training grant, one NIAAA K01 award and one NIAAA K99 award. Training and information dissemination to the San Diego community will be effected by the training opportunities of the Center including an NIAAA training grant and the Education Component.